title: Inhibition of pyrimidine biosynthesis pathway suppresses viral growth through innate immunity.
abstract: Searching for stimulators of the innate antiviral response is an appealing approach to develop novel therapeutics against viral infections. Here, we established a cell-based reporter assay to identify compounds stimulating expression of interferon-inducible antiviral genes. DD264 was selected out of 41,353 compounds for both its immuno-stimulatory and antiviral properties. While searching for its mode of action, we identified DD264 as an inhibitor of pyrimidine biosynthesis pathway. This metabolic pathway was recently identified as a prime target of broad-spectrum antiviral molecules, but our data unraveled a yet unsuspected link with innate immunity. Indeed, we showed that DD264 or brequinar, a well-known inhibitor of pyrimidine biosynthesis pathway, both enhanced the expression of antiviral genes in human cells. Furthermore, antiviral activity of DD264 or brequinar was found strictly dependent on cellular gene transcription, nuclear export machinery, and required IRF1 transcription factor. In conclusion, the antiviral property of pyrimidine biosynthesis inhibitors is not a direct consequence of pyrimidine deprivation on the virus machinery, but rather involves the induction of cellular immune response.
authors.affiliation: Institut Pasteur, Unité de Génomique Virale et Vaccination, Paris, France ; CNRS, UMR3569, Paris, France.
authors.forename: Marianne
authors.initials: M
authors.lastname: Lucas-Hourani
authors.forename: Daniel
authors.initials: D
authors.lastname: Dauzonne
authors.forename: Pierre
authors.initials: P
authors.lastname: Jorda
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Cousin
authors.forename: Alexandru
authors.initials: A
authors.lastname: Lupan
authors.forename: Olivier
authors.initials: O
authors.lastname: Helynck
authors.forename: Grégory
authors.initials: G
authors.lastname: Caignard
authors.forename: Geneviève
authors.initials: G
authors.lastname: Janvier
authors.forename: Gwénaëlle
authors.initials: G
authors.lastname: André-Leroux
authors.forename: Samira
authors.initials: S
authors.lastname: Khiar
authors.forename: Nicolas
authors.initials: N
authors.lastname: Escriou
authors.forename: Philippe
authors.initials: P
authors.lastname: Desprès
authors.forename: Yves
authors.initials: Y
authors.lastname: Jacob
authors.forename: Hélène
authors.initials: H
authors.lastname: Munier-Lehmann
authors.forename: Frédéric
authors.initials: F
authors.lastname: Tangy
authors.forename: Pierre-Olivier
authors.initials: PO
authors.lastname: Vidalain
mesh_terms: D018354:Alphavirus Infections / Q000188:drug therapy / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D065632:Chikungunya Fever; D002646:Chikungunya virus / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D002522:Chlorocebus aethiops; D006367:HeLa Cells; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects* / Q000276:immunology; D050856:Interferon Regulatory Factor-1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D011743:Pyrimidines / Q000096:biosynthesis* / Q000276:immunology; D014709:Vero Cells
chemical_list: D000998:Antiviral Agents; C494257:IRF1 protein, human; D050856:Interferon Regulatory Factor-1; D011743:Pyrimidines; C030986:pyrimidine